Compressed tablets for such uses as oral drug delivery are prepared by three methods--wet granulation, dry granulation and direct compression. Each method involves mixing powdered drug substance with a powdered binder material and compressing the mixture in a tableting machine. In the wet granulation method the mixture is granulated before compression by wetting with a solution of the binder while stirring, wet screening, drying and dry screening. In the dry granulation method the mixture is granulated before compression by dry-compacting then dry screening. In the direct compression method the powder mixture is compressed to form the tablet without intermediate granulation.
Binders which are used commercially in the manufacture of compressed tablets include lactose, hydroxypropylmethylcellulose, microcrystalline cellulose, acacia mucilage, tragacanth mucilage, starch mucilage, alginates, sugar and polyvinyl-pyrrolidone. Commercial prolonged-action tablets include tablets with slow-release cores, tableted mixed-release granules, multiple-layer tablets, drug-filled porous inert plastic pellets, and tablets of drug-ion exchange resin complexes. These are relatively complex formulations compared to conventional quick-release tablets and are thus more costly to manufacture. U.S. Pat. Nos. 3,870,790, 4,226,849 and 4,389,393 disclose sustained-release tablets made by conventional tablet-making methods using certain hydroxypropylmethylcelluloses (HPMC's) as binders. Although the HPMC's are being used commercially, their bulk flow characteristics and compressibility are rather poor; typically granulation prior to compression and high compression pressures are required, which may affect process and product reproducibility and add to the cost of manufacture.
Suess, Pharmazie, 38, No. 7, 476-8 (1983) describes preparation of compressed tablets by the direct compression method using polyvinyl alcohol (PVA) and drug substance. Inclusion of various quantities of magnesium stearate to provide delayed release is described. Protracted release was correlated to addition of other excipients, i.e., potato starch and magnesium stearate, rather than inclusion of PVA. Physical and chemical characteristics of the PVA used are not described. However, most commercially available PVA, because of its method of manufacture, is only partially hydrolyzed and consists of non-spheroidal particles with size distribution such that more than 50% of the material is retained on a 60 mesh (0.246 mm opening) Tyler screen. Such PVA particles have erratic flow and compressibility characteristics.
PVA has also been used to prepare controlled release drug formulations other than compressed tablets. For example, Korsmeyer et al., Journal of Membrane Science, 9, 211-227 (1981) describes preparation of PVA gels containing drug substance for controlled drug release. The gels were made by swelling PVA in water, adding drug substance and cross-linking with glutaraldehyde. The PVA used by Korsmeyer et al. was Elvanol.RTM. grade 85-82 from E. I. du Pont de Nemours and Company, Wilmington, Del. Korsmeyer et al. describes this PVA as an amorphous and a tactic polymer with number average molecular weight Mn=52,800, poly-dispersity index Mw/Mn=2.14, and degree of hydrolysis=99.8%. Keith et al. U.S. Pat. No. 4,291,014 discloses dissolving PVA and polyvinylpyrrolidone in water, adding a drug substance and pouring the mixture into forms to provide a diffusion matrix for controlled drug release. Numerous patents and published applications disclose controlled release oral formulations comprising drug substance in powder, pill, tablet or capsule form having a polymer coating comprising PVA. Examples of such patents and applications are PCT publication Nos. WO 85/03436, WO 85/03437, EPO publication Nos. 0 063 014; 0 076 428; U.S. Pat. Nos. 4,205,060, 4,432,965; and U.K. publication No. GB 2042892A. German published application No. 30 42 916 discloses a tablet made by applying a drug to the surface of a film of polyvinyl alcohol or a fiber fleece bonded with polyvinyl alcohol.
Compressed tablets containing other active ingredients such as, for example, pesticides or herbicides; fertilizers, especially for use on house plants; personal care products such as, for example, denture cleaners; household preparations such as, for example, bathroom cleaners, have been used to a lesser degree, either because of the high cost of tableting those materials relative to their value in use or because of the difficulty in controlling the rate of release of the active ingredient to the desired extent.
Tableting agricultural formulations such as, e.g., pesticides or herbicides offers many advantages over the usual dusts, powders, and granules. For example, tableting does not adversely affect heat-labile materials since it requires no heat; it prevents or reduces health and environment hazards encountered in the case of dusts and powders (and even granules); and it permits release of the active ingredient at a controlled rate.
Herbicides often are added in fertilizer solutions. Currently, they are supplied as dry flowable powders, which must be measured by the farm operator before adding to the fertilizer spray tank. This causes waste and exposes the operator to a biologically active material. Herbicides used for crop dusting need to have increased density and very specific geometry for accurate application.
Slugs are a serious pest to crops in many parts of the world. Current slug baits, consisting of wheat flour, pesticide, and paraffin wax binder, break up rapidly on exposure to damp earth and rain. A longer release slug bait would be very desirable.
Tableting solves all the above problems of the current agricultural formulations.
Industrial chemicals such as, e.g., oxidizing agents used for the purification and sanitation of spas and swimming pools normally are rapidly released into water shortly after their application. It would be desirable to control the rate of their release in order to minimize the frequency of their application and to avoid wide fluctuations in concentration.
Personal care products such as, e.g., denture cleaners and contact lens cleaners in tablet form permit the user to employ a predetermined effective amount of the active ingredient.
Veterinary chemicals in tablet form permit controlled release of nutritional supplements for animals such as dairy and beef cattle.